The research proposed here investigates a possible mechanism by which noradrenergic neurons in the brain influence dopaminergic neurons to produce behavioral changes seen in depression. These studies address an important issue related to the neurobiology of depression; namely, that while much evidence shows brain norepinephrine (NE) is important in both the pathogenesis and therapy of depression, basic research implicates dopamine (DA) in depression-related responses (motor activity changes, hedonic responses) much more so than NE. The proposed research derives from, and will continue to use, an animal (rat) model of depression that reproduces characteristics of clinical depression by exposing animals to uncontrollable stressful conditions (called "stress-induced behavioral depression"). Behavioral depression in this model has been traced to heightened "burst" firing of locus coeruleus (LC) neurons. The proposed hypothesis, based on recent electrophysiological data, is that the rapid firing of LC neurons releases galanin (GAL) from LC-NE terminals in the ventral tegmentum (VTA), which inhibits activity of DA cells that project to forebrain. Because VTA DA neurons mediate motor activity and reward processes, their inhibition causes changes seen in depression (i.e., psychomotor retardation and anhedonia). In testing this hypothesis, previous work has shown that microinjection of GAL into VTA mimics behavioral depression. Studies proposed here will determine if (1), conversely, blockade of GAL receptors in VTA can reverse behavioral depression, and (2) commensurate changes in extracellular DA (measured by microdialysis) in forebrain also occur. Next, using newly developed animal models that show (a) long-lasting behavioral depression, and (b) sensitivity and selectivity for responding to antidepressant treatments, studies are proposed to (1) measure monoamine (DA, NE, 5-HT) changes in forebrain in the model of long-lasting depression, (2) determine whether therapy for the long-lasting behavioral depression occurs if one blocks GAL receptors in VTA, and (3) measure effects of antidepressant treatments (drugs and electroconvulsive shock) on (i) electrophysiological activity of LC neurons (since GAL is released at high rates of depolarization), (ii) GAL in VTA and other LC projection regions (by measuring GAL in extracellular fluid and tissue) and GAL mRNA in LC, and (iii) extracellular DA (and other monoamines) in forebrain regions. By focusing on GAL, potential new transmitter involved in the pathogenesis of depression, a novel target for therapeutic intervention in this disorder may emerge.